Methods for Treating Gout Flares

ABSTRACT

Methods of treating gout flares comprising administering a composition comprising a first urate-lowering agent are disclosed. In some aspects, the first urate-lowering agent is (−)-halofenate, (−)-halofenic acid, or a pharmaceutically acceptable salt thereof. Other aspects provide for methods of reducing the number, duration, frequency or intensity of gout flares experienced by a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/556,052 filed on Nov. 4, 2011, the complete disclosure of which isincorporated by reference herein.

BACKGROUND

This application relates to the treatment, including the prevention, ofgout flares.

SUMMARY

This application describes methods of treating a gout flare experiencedby a subject comprising administering to the subject a compound ofFormula (I)

wherein R is selected from the group consisting of a hydroxy, loweraralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido-loweralkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-loweralkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxysubstituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-loweralkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substitutedlower alkylamino, hydroxy substituted lower alkylamino, loweralkanolyloxy substituted lower alkylamino, ureido, and loweralkoxycarbonylamino; and each X is independently a halogen, or apharmaceutically acceptable salt thereof.

Other aspects provide for methods of reducing the number, duration,frequency or intensity of gout flares experienced by a subjectcomprising administering a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof to the subject. Other aspects provide for thetreatment of hyperuricemia in a subject with gout comprisingadministering to a subject in need thereof a compound of Formula (I),wherein the dose, frequency, and duration of administration areeffective to reduce the number, duration, frequency, or intensity ofgout flares experienced by the subject during the duration. Yet otheraspects provide for methods of providing to a subject (−)-halofenic acidwith an intraday peak-to-trough ratio of about 2.0 or less. Furtheraspects are provided below.

Uric acid lowering agents such as allopurinol and febuxostat generallyincrease the number, duration, frequency, or intensity of gout flaresupon initiation of therapy, and this exacerbation may last for severalweeks to months following initiation of such therapy. Uric acid loweringagents often require a dose titration strategy in which the dose isprogressively increased to the therapeutic dose in order to minimize thenumber, duration, frequency, or intensity of flares. Flare treatment orprophylaxis with an additional therapeutic agent such as a non-steroidalanti-inflammatory agent (NSAID) or colchicine is often recommendedduring this period. During longer term maintenance use of urate loweringtherapy, flares can also be precipitated by fluctuations in uric acidlevels caused by non-adherance with prescribing instructions. Advantagesof the current methods include decreasing the number, duration,frequency, or intensity of flares experienced by the patient (e.g.during initiation or maintenance of therapy for uric acid lowering),decreasing the need for dose titration, and reducing the amount orduration of additional anti-flare medicaments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the mean trough plasma concentration values of(−)-halofenic acid during and following a 30-day dosing schedule ofdaily oral administration of 400 mg of arhalofenate.

FIG. 2 is a graph showing the mean and standard deviation (SD) of(−)-halofenic acid plasma concentrations at Day 15 and Day 30 followingdaily oral administration of 400 mg of arhalofenate in 20 humansubjects.

FIG. 3 is a graph showing reduction in serum uric acid in subjects overtime following once daily dosing with arhalofenate.

FIG. 4 is a chart showing the effect of the administration of(−)-halofenate on the incidence of gout flares in human subjects. “Pbo”means placebo; dosage information refers to the daily dosage of(−)-halofenate.

FIG. 5 is a chart showing the effect of the administration of(−)-halofenate on flare duration in human subjects. “Pbo” means placebo;dosage information refers to the daily dosage of (−)-halofenate.

FIG. 6 is a chart showing the effect of febuxostat alone and concomitantadministration of febuxostat and (−)-halofenate on the incidence of goutflares in human subjects presented as percentage of patients experiencedany flare per week.

FIG. 7 is a chart showing the effect of febuxostat alone and concomitantadministration of febuxostat and (−)-halofenate on flare duration inhuman subjects.

DETAILED DESCRIPTION

As utilized in accordance with the present disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

“About” when qualifying a number, refers to a range of plus or minus tenpercent of that value or number, unless indicated otherwise. Withoutlimiting the application of the doctrine of equivalents as to the scopeof the claims, each number should be construed in light of such factorsas the number of reported significant digits and the manner or method(e.g. instrumentation, sample preparation, etc.) used to obtain thatnumber.

“Administering” or “administration” refers to the act of giving a drug,prodrug, or therapeutic agent to a subject. Exemplary routes ofadministration are discussed below.

“Acute gout” refers to gout present in a subject with at least one goutysymptom (e.g., podagra or other gouty arthritis, gout flare, goutyattack).

“Chronic gout” refers to gout present in a subject having recurrent orprolonged gout flares, tophus formation, chronic inflammatory arthritis,or joint deterioration associated with gout, and includes the periodsfollowing recovery from acute gout and between acute gout attacks (i.e.intercritical gout).

“Composition” or, interchangeably, “formulation” refers to a preparationthat contains a mixture of various excipients and key ingredients thatprovide a relatively stable, desirable, and useful form of a compound ordrug.

The terms “combination therapy,” “concomitantly administering” and“concomitant administration” refer to the administration of two or moreagents in any manner in which the pharmacological effects of thoseagents are manifested in the subject at the same time. These termsencompass administering two or more agents to a subject substantiallyconcurrently, for example in a single dosage form (e.g. a singlecapsule, pill, tablet, etc.), administering at least one agent in onedosage form and the other agent(s) in a separate dosage form, andadministering each agent in its own separate dosage form. Theadministration may be performed sequentially or simultaneously. Forexample, for sequential administration, the first agent may beadministered before or after the second agent.

The prefixes “d” and “1” or (+) and (−) are employed to designate thesign of rotation of plane-polarized light by the compound, with (+) ord− meaning that the compound is “dextrorotatory” and with (−) or l−meaning that the compound is “levorotatory”. For a given chemicalstructure, these isomers or “optical isomers” are identical except thatthey are mirror images of one another. In describing an optically activecompound, the prefixes R and S are used to denote the absoluteconfiguration of the molecule about its chiral center(s). There is nocorrelation between the nomenclature for the absolute stereochemistryand for the rotation of an enantiomer (i.e., the R— isomer can also bethe 1-isomer). A specific optical isomer can also be referred to as an“enantiomer,” and a mixture of such isomers is often called an“enantiomeric” or “racemic” mixture. See, e.g., A. Streitwiesser & C. H.Heathcock, INTRODUCTION TO ORGANIC CHEMISTRY, 2^(nd) Edition, Chapter 7(MacMillan Publishing Co., U.S.A. 1981). The optical rotation [α]_(D) of(−)-halofenate was measured in methyl alcohol.

“Elevated serum uric acid level” refers to a serum uric acid levelgreater than normal and, in patients with gout, generally refers to aserum uric acid level greater than or equal to about 6 mg/dL. In someinstances, elevated serum uric acid levels are above the mean level in agiven population, such as those of a particular gender or age.

“Effective amount” refers to an amount required (i) at least partly toattain the desired response in a subject; (ii) to delay or to preventthe onset of a particular condition being treated in a subject; or (iii)or to inhibit or to prevent the progression of a particular conditionbeing treated in a subject. The effective amount for a particularsubject varies depending upon the health and physical condition of thesubject to be treated, the taxonomic group of individual to be treated,the degree of protection desired, the formulation of the composition,the assessment of the medical situation, and other relevant factors. Itis expected that the amount will fall in a relatively broad range thatcan be determined through routine trials.

“First urate-lowering agent” refers to a compound of any of Formula (I),(II), (III) or (IV) or a therapeutically acceptable salt or prodrugthereof. For clarity, this term implies no temporal aspect orrelationship, e.g. to a second urate-lowering agent.

“Flare” or “gout flare” refers to a symptom of gout associated with asudden onset of pain and inflammation, especially in peripheral jointssuch as the toes or fingers.

“Gout” refers to a group of disorders or symptoms most often associatedwith the accumulation of uric acid due to an overproduction of uric acidor a reduced ability of the kidney to excrete uric acid. Gout is oftencharacterized by the deposition of urate crystals (uric acid or saltsthereof, e.g. monosodium urate) in the joints (gouty arthropathy) orsoft tissue (tophi).

“Gout” as used herein includes acute gout, chronic gout, moderate gout,refractory gout and severe gout.

“Gout-associated inflammation” refers to local or systemic inflammationdue to immune responses to the deposition of urate crystals.

“Halofenate” refers to compounds of Formula (III) below, i.e.(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid2-acetylaminoethyl ester (also referred to as the 2-acetamidoethyl esterof 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid). The termhalofenate and the corresponding chemical names include both the (+) and(−) enantiomer of compounds of Formula (III) as well as mixturesthereof, unless otherwise specified.

“Halofenic acid” and “CPTA” refer to the compounds of Formula (IV), i.e.4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid [also referred toas 2-(4-chlorophenyl)-2-(3-(trifluoromethyl)phenoxy)acetic acid] as wellas its pharmaceutically acceptable salts. The term halofenic acid andthe corresponding chemical names include both the (+) and (−) enantiomerof compounds of Formula (IV) as well as mixtures thereof, unlessotherwise specified.

“Hyperuricemia” refers to an elevated serum uric acid level (see above).

“Impaired renal function” refers to a medical condition in which thekidneys fail to adequately filter toxins and waste products from theblood. Impaired renal function may take the form or acute kidney injuryor chronic kidney disease (i.e. CKD1-5).

“Moderate gout” refers to gout present in a subject having at least twogout flares in the past 12 months.

“Pharmaceutically acceptable” refers to that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and neither biologically nor otherwise undesirable, andincludes that which is acceptable for veterinary or human pharmaceuticaluse.

“Pharmaceutically acceptable salt” includes pharmaceutically acceptableacid addition salts and pharmaceutically acceptable base addition saltsand includes both solvated and unsolvated forms. Representativenon-limiting lists of pharmaceutically acceptable salts can be found inS. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington:The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition,Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p. 732,Table 38-5, both of which are hereby incorporated by reference herein.

“Pharmaceutically acceptable acid addition salt” refers to salts formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to saltsprepared from the addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like.

“Refractory gout” refers to gout in patients who are unresponsive orpoorly responsive to one or more second urate-lowering agents, or haveexperienced or are at an increased risk of experiencing an adverse eventtherefrom. The terms “unresponsive” and “poorly responsive” in thiscontext include (1) no or insignificant lowering of serum uric acid, (2)failure to reach a target serum uric acid level (e.g. as determined by aphysician or other medical practitioner), and (3) the persistence of oneor more gouty conditions or symptoms such as gout flares, gouty tophus,gouty arthritis, or other associated conditions regardless of anylowering of serum uric acid levels.

“Second urate-lowering agent” refers to a therapeutic agent that lowersserum uric acid levels that is not a first urate-lowering agent. Secondurate-lowering agents include currently available agents (i.e. an agentapproved by the FDA or other appropriate regulatory authority as of thefiling date of this application) that lower serum uric acid, as well ascompounds currently in development or under regulatory review. Examplesof second urate-lowering agents are provided below. For clarity, thisterm implies no temporal aspect or relationship, e.g. to a firsturate-lowering agent.

“Subject” and “patient” refer to animals such as mammals, includinghumans, other primates, domesticated animals (e.g. dogs, cats), farmanimals (e.g. horses, cattle, goats, sheep, pigs), rats and mice.

“Severe gout” refers to gout present in a subject having tophaceousdeposits in the joints, skin, or kidneys resulting in chronic arthritis,joint destruction, subcutaneous tophi, or kidney dysfunction, and, insome cases, with subsequent deformity and/or disability.

“Substantially free from” when used in reference to (−)-halofenate or(−)-halofenic acid (or a salt thereof) being substantially free from thecorresponding (+) enantiomer (i.e. (+)-halofenate, (+)-halofenic acid,or a salt thereof) refers to a composition containing a high proportionof a compound's (−) enantiomer in relation to the (+) enantiomer. In oneembodiment, the term means that by weight, the compound included in thecomposition is at least 85% (−) enantiomer and at most 15% (+)enantiomer. In one embodiment, the term means that by weight, thecompound included in the composition is at least 90% (−) enantiomer andat most 10% (+) enantiomer. In other embodiments, the term means that byweight, the compound included in the composition is at least 91% (−)enantiomer and at most 9% (+) enantiomer, at least 92% (−) enantiomerand at most 8% (+) enantiomer, at least 93% (−) enantiomer and at most7% (+) enantiomer, at least 94% (−) enantiomer and at most 6% (+)enantiomer, at least 95% (−) enantiomer and at most 5% (+) enantiomer,at least 96% (−) enantiomer and at most 4% (+) enantiomer, at least 97%(−) enantiomer and at most 3% (+) enantiomer, at least 98% (−)enantiomer and at most 2% (+) enantiomer, or at least 99% (−) enantiomeror greater than 99% (−) enantiomer. Other percentages of the (−) and (+)enantiomers may also be provided. These percentages are based upon theamount of the enantiomer relative to the total amount of bothenantiomers of the compound in the composition.

“Therapeutically effective dose”, “therapeutically effective amount”,or, interchangeably, “pharmacologically acceptable dose” and“pharmacologically acceptable amount” mean that a sufficient amount of atherapeutic agent, therapeutic agents, or metabolites thereof will bepresent in order to achieve a desired result, e.g., lowering uric acidlevels to a target goal or treating gout in its various forms ortreating conditions associated with hyperuricemia.

“Treatment” and “treating” of a disease, disorder, condition or symptomrefer to (1) preventing or reducing the risk of developing the disease,disorder or condition, i.e., causing the clinical symptoms of thedisease, disorder or condition not to develop in a subject who may beexposed to or predisposed to the disease, disorder or condition but whodoes not yet experience or display symptoms of the disease, disorder orcondition (i.e. prophylaxis); (2) inhibiting the disease, disorder orcondition, i.e., arresting or reducing the development of the disease,disorder or condition or its clinical symptoms; and (3) relieving thedisease, disorder or condition, i.e., causing regression, reversal, oramelioration of the disease, disorder or condition or reducing thenumber, duration, frequency or intensity one or more of its clinicalsymptoms (e.g. a gout flare). The term “management” may be usedsynonymously.

“Urate” refers to uric acid (7,9-dihydro-1H-purine-2,6,8(3H)-trione) andions and salts thereof.

This application describes methods of treating a gout flare comprisingadministering to the subject a compound of Formula (I)

wherein R is selected from the group consisting of a hydroxy, loweraralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido-loweralkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-loweralkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxysubstituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-loweralkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substitutedlower alkylamino, hydroxy substituted lower alkylamino, loweralkanolyloxy substituted lower alkylamino, ureido, and loweralkoxycarbonylamino; and each X is independently a halogen, or apharmaceutically acceptable salt thereof.

In certain aspects, the compound is a compound of Formula (II)

wherein R² is selected from the group consisting of phenyl-lower alkyl,lower alkanamido-lower alkyl, and benzamido-lower alkyl; and each X isindependently a halogen, or a pharmaceutically acceptable salt thereof.

In other aspects, the compound is a compound of Formula (III), alsoreferred to as halofenate

or a pharmaceutically acceptable salt thereof.

In other aspects, the compound is a compound of Formula (IV), alsoreferred to as halofenic acid

or a pharmaceutically acceptable salt thereof.

It should be noted that any carbon atom with unsatisfied valences in theformulae and examples herein is assumed to have the hydrogen atom tosatisfy the valences.

In certain embodiments the compound is a compound that generates thecompound of Formula (IV) or a pharmaceutically acceptable salt thereofvia a chemical reaction after being administered, as discussed in moredetail below.

In certain embodiments, the compound is the (−) enantiomer of a compoundof Formula (I), (II), (III) or (IV). In certain embodiments, thecompound is (−)-halofenate (i.e.(−)-(R)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid2-acetylamino-ethyl ester, also referred to as arhalofenate). In otherembodiments, the compound is (−)-halofenic acid (i.e.(−)-4-chlorophenyl-(3-trifluoromethylphenoxy)acetic acid) or apharmaceutically acceptable salt thereof. In certain embodiments, the(−)-halofenate, (−)-halofenic acid, or pharmaceutically acceptable saltthereof is substantially free from the corresponding (+) enantiomer.

The enantiomers (stereoisomers) of compounds of Formula (I), (II), (III)or (IV) and pharmaceutically acceptable salt thereof can be prepared byusing reactants or reagents or catalysts in their single enantiomericform in the process wherever possible or by resolving the mixture ofstereoisomers by conventional methods including use of microbialresolution, resolving the diastereomeric salts formed with chiral acidsor chiral bases and chromatography using chiral supports. See, also U.S.Pat. No. 7,199,259 (Daugs), U.S. Pat. Nos. 6,646,004; 6,624,194;6,613,802; and 6,262,118 (each to Luskey et al.), U.S. Pat. No.7,714,131 (Zhu et al.), U.S. Pat. No. 7,432,394 (Cheng et al.) and U.S.Publication No. 2010/0093854 (Broggini et al.) each of which areincorporated herein by reference in their entireties.

The chemical synthesis of racemic mixtures of (3-trihalomethylphenoxy)(4-halophenyl) acetic acid derivatives can also be performed by themethods described in U.S. Pat. No. 3,517,050, the teachings of which areincorporated herein by reference. The individual enantiomers can beobtained by resolution of the racemic mixture of enantiomers usingconventional means known to and used by those of skill in the art. See,e.g., J. Jaques et al., in ENANTIOMERS, RACEMATES, AND RESOLUTIONS, JohnWiley and Sons, New York (1981). Other standard methods of resolutionknown to those skilled in the art, including but not limited to, simplecrystallization and chromatographic resolution, can also be used (see,e.g., STEREOCHEMISTRY OF CARBON COMPOUNDS (1962) E. L. Eliel, McGrawHill; J. Lochmuller, Chromatography 113, 283-302 (1975)). Additionally,halofenate, halofenic acid, or a pharmaceutically acceptable saltthereof, i.e., the optically pure isomers, can be prepared from theracemic mixture by enzymatic biocatalytic resolution. Enzymaticbiocatalytic resolution has been generally described previously (see,e.g., U.S. Pat. Nos. 5,057,427 and 5,077,217, the disclosures of whichare incorporated herein by reference). Other generic methods ofobtaining enantiomers include stereospecific synthesis (see, e.g., A. J.Li et al., Pharm. Sci. 86, 1073-1077 (1997)).

FIGS. 1-2 show the pharmacokinetic profile of (−)-halofenic acid. FIG. 1shows the mean trough plasma concentration values of (−)-halofenic acidduring and following a 30-day dosing schedule of daily oraladministration of 400 mg of arhalofenate. FIG. 2 shows the mean andstandard deviation (SD) plasma concentration values of (−)-halofenicacid at day 15 and day 30 following daily oral administration of 400 mgof arhalofenate. These figures demonstrate a long half-life withsustained drug levels present for several days after the final dose, anda relatively constant intraday plasma concentration. The plasmaconcentration of (−)-halofenic acid is expected to correlate to theplasma concentration of uric acid. Accordingly, the long half-life andlow intraday peak-to-trough ratio are expected to result incorrespondingly gradual changes in serum uric acid during the initiationof and maintenance use of therapy. FIG. 3 demonstrates the reduction inserum uric acid over time with several doses of arhalofenate, andsupports this theory. It is thought that large or rapid changes in serumuric acid (resulting from, for example, the administration of certainsecond urate-lowering agents, e.g. allopurinol, febuxostat, and otherswhen no first urate-lowering agent is administered) can trigger goutflares or result in longer, more frequent, or more intense flares, forexample during and for the several weeks and months after initiation ofsuch agents, or with non-adherance to daily use of such agents.Therefore, the pharmacokinetic profile of (−)-halofenic acid shouldcontribute to the successful use of compounds of Formula (I), (II),(III) or (IV) and pharmaceutically acceptable salts thereof in theprevention of gout flares (for example, during certain durations such asthe first several weeks to month after initiation of administration),compared to other urate lowering therapies.

Methods described herein include reducing the number, duration,frequency or intensity of one or more gout flares, the methodscomprising administering to a subject in need thereof a compound of anyof Formula (I), (II), (III) or (IV) or a pharmaceutically acceptablesalt thereof. In some embodiments the compound is (−)-halofenate,(−)-halofenic acid or a pharmaceutically acceptable salt thereof. Insome embodiments, the number, duration, frequency or intensity of goutflares experienced by the subject is reduced relative to thatexperienced by the subject before such administration is initiated. Inother embodiments, the number, duration, frequency or intensity of goutflares experienced by the subject is reduced relative to the number,duration, frequency or intensity of gout flares experienced by thesubject when the subject has previously undergone urate-lowering therapywith a second urate-lowering agent. In some embodiments, the methodsdescribed herein are for the prevention of flares. In some embodiments,the methods described herein are for the prophylaxis of flares.

In certain methods described herein, a compound of Formula (I) and aflare prophylaxis or pain management agent (including, but not limitedto, a non-steroidal anti-inflammatory drug (NSAID), an opiate, orcolchicines, and wherein such agent is not a compound of Formula (I))can be concomitantly administered to the subject. In certain methods,the amount or duration of administration of such flare prophylaxis orpain management agent is reduced (as compared to when no compound ofFormula (I) is administered), and in other methods no such flareprophylaxis or pain management agent is administered.

The second urate-lowering agent may be any agent that lowers serum uricacid levels that is not a first urate-lowering agent (i.e. not acompound of any of Formula (I), (II), (III) or (IV) or apharmaceutically acceptable salt thereof). These second urate-loweringagents include inhibitors of uric acid production (e.g. xanthine oxidaseinhibitors and purine nucleoside phosphorylase inhibitors), uricosuricagents, and uricases. Xanthine oxidase inhibitors include, but are notlimited to: allopurinol, febuxostat, oxypurinol, tisopurine, an inositoland propolis. In some embodiments, the xanthine oxidase inhibitor isallopurinol, febuxostat, oxypurinol, tisopurine, inositol, phytic acid,myo-inositiol, kaempferol, myricetin, and quercetin. Allopurinol(1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a xanthine oxidaseinhibitor, is the current first line standard of care for lowering uratelevels. Another xanthine oxidase inhibitor, febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid),was approved for treatment of gout in February 2009. Purine nucleosidephosphorylase (PNP) inhibitors represent a relatively new approach tolowering serum uric acid levels in patient with hyperuricemia, gout, andrelated conditions. In some embodiments, the PNP inhibitor is forodesine(BCX1777) (BioCryst Pharmaceuticals, Inc.). In other embodiments, thePNP inhibitor is ulodesine (BCX4208;7-(((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one)(BioCryst Pharmaceuticals, Inc.). Ulodesine monotherapy administered at40, 80, 120, 160 and 240 mg/day has been shown to rapidly andsignificantly reduced serum uric acid in gout patients. Uricosuricagents enhance renal excretion of uric acid and generally act bylowering the absorption of uric acid from the kidney proximal tubuleback to the blood, e.g., by inhibiting urate transporters, e.g,SLC22A12. Uricosuric agents include, but are not limited to, probenecid,2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)aceticacid (RDEA594, lesinurad), potassium4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetamido)-3-chlorobenzoate(RDEA806), RDEA684, benzbromarone, sulfinpyrazone, amlodipine,atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropichormone, and cortisone. Probenecid is the most commonly used uricosuricagent in the U.S. and may be given in combination with allopurinol tosome gout patients. Benzbromarone and sulfinpyrazone are also used asfirst line uricosuric agents. Guaifenesin, losartan, atorvastatin,amlodipine, adrenocorticotropic hormone (ACTH or corticotropin),fenofibrate, levotofisopam, and cortisone also have uricosuric effects.Uricase or urate oxidase enzymes are found in many mammals but nothumans. They can lower uric acid levels by converting uric acid intoallantoin, a benign end metabolite which is easily excreted in theurine. Uricase enzymes include, but are not limited to, rasburicase or apegylated uricase enzyme (PEG-uricase). In some embodiments, thepegylated uricase enzyme is Krystexxa® (PURICASE®; pegloticase) (SavientPharmaceuticals, Inc.) which is approved in the U.S. for the treatmentof chronic gout in adult patients refractory to conventional therapy.

In some embodiments, the number of gout flares experienced by thesubject is reduced relative to the number, duration, frequency orintensity of gout flares experienced by the subject when the subject haspreviously undergone urate-lowering therapy with a second urate-loweringagent, wherein the second urate-lowering agent is allopurinol,febuxostat, lesinurad or BCX4208.

Certain methods provide for the treatment or management of hyperuricemiain a subject with gout and reducing the number, duration, frequency orintensity of gout flares experienced by the subject. These methodscomprise administering to a subject in need thereof a compound of any ofFormula (I), (II), (III) or (IV) or a pharmaceutically acceptable saltthereof. In some embodiments the compound is (−)-halofenate,(−)-halofenic acid or a pharmaceutically acceptable salt thereof.

FIGS. 4-5 show the effect of (−)-halofenate monotherapy on gout flaresin human subjects. Referring to FIG. 4, the administration of(−)-halofenate dose dependently reduced the incidence of any flares(Total flare) and flares requiring treatment compared to placebo(presented as percentage of patients experienced any flares (totalflare) and flares requiring treatment by treatment arm). Referring toFIG. 5, the administration of (−)-halofenate also reduced the durationof all flares (any flares and flares requiring treatment). See Examplebelow for more details.

FIGS. 6-7 show the effect of concomitant administration of(−)-halofenate with febuxostat (a second urate-lowering agent, asdescribed herein), compared to the administration of febuxostat with noother urate-lowering agent (“Febuxostat Alone”) on gout flares in humansubjects. Referring to FIG. 6, the concomitant administration of(−)-halofenate and febuxostat reduced flare incidence as compared to theadministration of febuxostat without (−)-halofenate.

FIG. 7 shows that such concomitant administration also reduced theduration of flares. See Example below for more details.

In various embodiments, the methods described herein lower serum uricacid levels in a subject by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90% or more, as compared to serum uric acid levels in the subjectprior to administering the methods described herein. In variousembodiments, serum uric acid levels are decreased about 5% to about 50%,decreased by about 25% to about 75%, or decreased by about 50% to about99%. Methods to determine serum uric acid levels are well known in theart and are often measured as part of a standard chemistry panel ofblood serum samples.

In some embodiments, the methods of the present disclosure lower serumuric acid levels in a subject to about 7 mg/dL or less, to about 6.5mg/dL or less, to about 6 mg/dL or less, to about 5 mg/dL or less, toabout 4 mg/dL or less, or to about 3 mg/dL or less as compared to serumuric acid levels in the subject prior to administering the methods orcompositions described herein. In some embodiments, the methods of thepresent disclosure lower serum uric acid levels in a subject by 0.1,0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg/dL, or greater, ascompared to serum uric acid levels in the subject prior to administeringthe methods or compositions described herein. In further embodiments,the methods described herein lower serum uric acid levels by between 0.1and 10.0 mg/dL, between 0.5 and 6.0 mg/dL, between 1.0 and 4.0 mg/dL orbetween 1.5 and 2.5 mg/dL. The appropriate serum uric acid level mayvary depending on the subject, and may vary for a given subject overtime, depending upon the subject's overall medical condition. Similarly,the appropriate serum uric acid level for one group of subjects sharinga common medical condition may be different from that which isappropriate for a different group of subjects sharing a differentmedical condition. Thus, it may be advisable to reduce the serum uricacid level of a given group of subjects to, for example, below about 5mg/dL, and to reduce the serum uric acid level of a different group ofsubjects to, for example, below about 4 mg/dL. In certain embodiments,the methods of the present disclosure decrease a serum uric acid levelin the subject by an amount sufficient to result in the disappearance,reduction, amelioration, or the prevention of the onset, of one or moreconditions associated with elevated serum uric acid over a certaintimeframe, for example about a week, about a month, about six months,about one year, about two years, or for a longer duration. For example,a method can decrease the serum uric acid level in a subject by anamount sufficient to result in the disappearance or reduction of tophiover about one week, about one month, about six months, about one year,about two years, or longer, e.g. indefinitely, e.g. for the remainder ofthe lifetime of the subject.

In further embodiments, the methods of the present disclosure compriseadministering a pharmaceutical composition comprising a compound ofFormula (I), (II), (III) or (IV) or a pharmaceutically acceptable saltthereof to a subject whose serum uric acid level is at least about 4mg/dL, at least about 5 mg/dL, at least about 6 mg/dL, at least about6.8 mg/dL, at least about 7 mg/dL, at least about 8 mg/dL, at leastabout 9 mg/dL, at least about 10 mg/dL, or at least about 11 mg/dL.Again, the amount of decrease of serum uric acid level that isappropriate may vary depending on the subject, depending upon thesubject's overall medical condition. Similarly, the amount of decreaseof serum uric acid level that is appropriate for one group of subjectssharing a common medical condition may be different from that which isappropriate for a different group of subjects sharing a differentmedical condition.

The methods described herein (as well as the underlying physiologicalmechanisms related to them) may be accomplished by the administration ofa compound that generates the compound of Formula (IV) or a salt thereofvia a chemical reaction after being administered. Such compounds includeprodrugs of the compound of Formula (IV). Prodrugs of a compound areprepared by modifying functional groups present in the compound in sucha way that the modifications may be cleaved in vivo to release theparent compound, or an active metabolite. For example, prodrugs includecompounds wherein a hydroxy, amino or sulfhydryl group in a compound isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Certain prodrugs mayincrease the bioavailability of the compounds of the embodiments whensuch compounds are administered to a subject (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to an organ or tissue(e.g., adipose tissue, kidneys, liver, muscle, or joints) relative tothe parent species. More particularly, prodrugs of the compound ofFormula (IV) include esters, amides, and carbamates (e.g.,N,N-dimethylaminocarbonyl) of the hydroxy functional group of thecompound of Formula (IV). The compounds of Formulae (I), (II) and (III)are non-limiting examples of prodrugs of the compound of Formula (IV).Further examples of prodrugs can be found in J. Rautio et al. Prodrugs:design and clinical applications, Nat. Rev. Drug Discov., 7, 255-270(2008); Edward B. Roche, ed., Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, (1987); and T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series (1975), each of which are herebyincorporated by reference herein.

The compounds of Formulae (I), (II), (III) and (IV) and pharmaceuticallyacceptable salts thereof are contemplated to exhibit therapeuticactivity when administered in an amount which can depend on theparticular case. The variation in amount can depend, for example, on thesubject being treated and the active ingredients chosen. A broad rangeof doses can be applicable. Dosage regimes may be adjusted to providethe optimum therapeutic response. For example, several divided doses maybe administered daily, weekly, monthly or other at suitable timeintervals or the dose may be proportionally reduced as indicated by theexigencies of the situation. Such dosages are optionally altereddepending on a number of variables, not limited to the activity of theone or more active ingredients used, the disease or condition to betreated, the mode of administration, the requirements of the individualsubject, the severity of the disease or condition being treated, and thejudgment of the practitioner.

Depending on factors such as the diagnosis, symptoms, and therapeuticgoals of a particular subject, a wide range of dosages of the compoundof Formula (I), (II), (III) or (IV) can be contemplated. In variousembodiments, the compound may be administered from about 10 mg to about1000 mg per day. For example, halofenate, halofenic acid, or apharmaceutically acceptable salt thereof may be administered at about 50mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800mg/day, about 900 mg/day, or about 1000 mg/day.

Dose titration or dose escalation protocols may be employed to determinethe proper or optimal dose to administer to a subject. For example, dosetitration or escalation studies may select for doses that improveefficacy or tolerability. Dose titration or escalation allows for thegradual adjusting of the dose administered until the desired effect isachieved. Dose titration gradually decreased the dosage administeredwhile dose escalation gradually increases the dose administered. Methodsof dose titration and escalation are well known in the art. As anon-limiting example, a subject may be administered 200 mg/dayhalofenate, halofenic acid, or a pharmaceutically acceptable saltthereof every day and measured for serum uric acid levels on a dailybasis. The dosage may be increased or decreased, for example, on aweekly basis. The subject may be monitored for a period of, for example,2 to 12 weeks to find the desired dose.

Compounds of Formula (I), (II), (III) or (IV) can be incorporated into avariety of formulations and medicaments for therapeutic administration.More particularly, these compounds can be formulated into pharmaceuticalcompositions or formulations by combination with appropriate,pharmaceutically acceptable carriers or diluents, and can be formulatedinto preparations in solid, semi-solid, liquid or gaseous forms, such astablets, capsules, pills, powders, granules, dragees, gels, slurries,ointments, solutions, suppositories, injections, inhalants and aerosols.As such, administration of the compounds can be achieved in variousways, including oral, buccal, rectal, parenteral, intraperitoneal,intradermal, transdermal, or intratracheal administration. Moreover, thecompound can be administered in a local rather than systemic manner, ina depot or sustained release formulation. In addition, the compounds canbe administered in a liposome.

Compounds of Formula (I), (II), (III) or (IV) or a pharmaceuticallyacceptable salt thereof can also be formulated with common excipients,diluents or carriers and compressed into tablets, or formulated aselixirs or solutions for convenient oral administration, or administeredby the intramuscular or intravenous routes. The compounds can beadministered transdermally, and can be formulated as sustained releasedosage forms and the like. In one embodiment, the above methods mayfurther comprise the administration of a second urate-lowering agentselected from the group consisting of a xanthine oxidase inhibitor, aninhibitor of uric acid production, a uricosuric agent and a uricase. Inone embodiment, the method comprise administering a pharmaceuticalcomposition comprising a first urate-lowering agent and a secondtherapeutic agent, as described herein, to a subject whose serum uricacid level is at least about 4 mg/dL, at least about 5 mg/dL, at leastabout 6 mg/dL, at least about 6.8 mg/dL, at least about 7 mg/dL, atleast about 8 mg/dL, at least about 9 mg/dL, at least about 10 mg/dL, orat least about 11 mg/dL. The amount of decrease of serum uric acid levelthat is appropriate may vary depending on the subject, depending uponthe subject's overall medical condition. Similarly, the amount ofdecrease of serum uric acid level that is appropriate for one group ofsubjects sharing a common medical condition may be different from thatwhich is appropriate for a different group of subjects sharing adifferent medical condition.

In other embodiments, a first and a second urate-lowering agent (whereinthese first and second urate-lowering agents are described herein) canbe concomitantly administered. Such administration does not require thata single pharmaceutical composition, the same type of formulation, thesame dosage form, or even the same route of administration be used foradministration of both the first and second urate-lowering agents, orthat the two agents be administered at the same time. Suchadministration may be accomplished by the same dosage form and the sameroute of administration, at substantially the same time. For example, afirst urate-lowering agent, e.g. halofenate, halofenic acid, or apharmaceutically acceptable salt thereof, and a second urate-loweringagent, e.g. xanthine oxidase inhibitor (e.g., allopurinol orfebuxostat), can be administered to the subject together in a singleoral dosage composition, such as a tablet or capsule, or each agent canbe administered in separate oral dosage formulations. One advantage withseparate formulations is an added flexibility in dosing, i.e., thedosage of the first and second urate-lowering agents can be changedindependently, quickly, and easily. Where separate dosage formulationsare used, the first and second urate-lowering agents can be administeredat essentially the same time (i.e., simultaneously or concurrently), ordifferent times (i.e., sequentially). In various embodiments, the secondurate-lowering agent can be administered at from about 10 mg to about4000 mg per day. In certain embodiments, the second urate-lowering agentis a xanthine oxidase inhibitor, preferably selected from the groupconsisting of allopurinol, febuxostat, oxypurinol, tisopurine, inositol,phytic acid, myo-inositiol, kaempferol, myricetin, and quercetin,especially allopurinol or febuxostat. In certain embodiments, the secondurate-lowering agent is allopurinol and is administered at from about 50mg to about 800 mg per day. In other embodiments, the secondurate-lowering agent is febuxostat and is administered at from about 40mg to about 120 mg per day. For example, in certain embodiments, thefirst urate-lowering agent is (−)-halofenate and is administered at fromabout 100 mg to about 1000 mg per day, and the second urate-loweringagent is febuxostat and is administered at from about 40 mg to about 120mg per day. By way of further non-limiting examples wherein the firsturate-lowering agent is (−)-halofenate and wherein the secondurate-lowering agent is febuxostat, the following daily dosages may beadministered: arhalofenate 600 mg/day, febuxostat 40 mg/day;arhalofenate 600 mg/day, febuxostat 80 mg/day; arhalofenate 600 mg/day,febuxostat 120 mg/day; arhalofenate 800 mg/day, febuxostat 40 mg/day;arhalofenate 800 mg/day, febuxostat 80 mg/day; arhalofenate 800 mg/day,febuxostat 120 mg/day. In another embodiment, the second urate-loweringagent is a uricosuric agent, preferably selected from the groupconsisting of probenecid,2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, potassium4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetamido)-3-chlorobenzoate,RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin,fenofibrate, guaifenesin, losartan, adrenocorticotropic hormone andcortisone, especially probenecid.

Other dose ranges within the ranges described above for each of thefirst urate-lowering agent and the second urate-lowering agent may bereadily envisaged. One of skill in the art will appreciate that the doseand dosing regimen may be adjusted when therapeutic agents are used incombination. When such combinations are used, the dose of one or more ofthe agents may be reduced to a level below the level required for adesired efficacy when the one or more agents are used alone. Similarly,the dosing regimen may be modified, e.g., to synchronize the dosing ofthe one or more therapeutic agents to facilitate improved patient easeof use and compliance. Alternately, the dosing regimen of the one ormore therapeutic agents can be sequential, e.g., to reduce the combinedload of the agents at a given time. For example, in certain embodiments,the dose of the second urate-lowering agent (e.g. allopurinol,febuxostat, or the other second urate-lowering agents described herein)can be adjusted to a lower level than that currently recommended whenthe first urate-lowering agent is and second urate-lowering agents areadministered.

In various embodiments, compounds of Formula (I), (II), (III) or (IV) ora pharmaceutically acceptable salt thereof can be administered over abroad frequency range. For example, in various embodiments the compoundsmay be administered once daily (QD), twice daily (BID), three timesdaily (TID) or four times per day (QID). In one embodiment, the compoundis administered once daily (QD). In another embodiment, the compound isadministered twice daily (BID). In other embodiments, administration ofthe compound can be skipped without having deleterious effect, that is,the compound can be administered over (i.e. before and after) a “drugholiday” where the drug holiday is the period of the skipped dose. Forexample, in a daily dosing regimen, the compound can be administeredover a drug holiday of one day, (i.e. administered on day N and day N+2but not on day N+1, where day N is any arbitrary day) without thesubject experiencing any substantially or materially adverse effect fromthe skipped administration. In certain embodiments the drug holiday canbe two days. In other embodiments the drug holiday can be more than twodays.

In various embodiments, compounds of Formula (I), (II), (III) or (IV) ora pharmaceutically acceptable salt thereof can be administered over abroad duration. For example, in various embodiments the compounds may beadministered for about 10 days or longer, about four weeks or longer,about one month or longer, about 12 weeks or longer, about three monthsor longer, about six months or longer, about one year or longer, abouttwo years or longer, about five years or longer, or about 10 years orlonger. In some embodiments the administration may be indefinite, e.g.for the remainder of the lifetime of the subject.

The pharmacokinetic profile of (−)-halofenic acid can be modulated bythe dose, frequency, and duration of administration of the compound or aprodrug thereof. One measure of the pharmacokinetic profile is thepeak-to-trough ratio, defined as the highest blood plasma concentrationdivided by the lowest blood plasma concentration of a compound or agentwithin a certain time interval (e.g. within the interval correspondingto the frequency of administration). For example, certain methodsinclude providing to a subject an intraday peak-to-trough ratio of(−)-halofenic acid of about 2.0 or less, comprising administering to thesubject a compound of Formula (I), (II), (III) or (IV) orpharmaceutically acceptable salts thereof at a dose of about 100 toabout 1000 mg per day. In various embodiments, the intradaypeak-to-trough ratio is about

-   1.7 or less, about 1.5 or less, about 1.4 or less, or about 1.3 or    less. In embodiments, the intraday peak-to-trough ratio is provided    after administering the compound daily for at least about 10 days,    e.g. at least about 12 days. The pharmacokinetic profile can also    depend on the route of administration, as well as by the compound    and formulation administered to the subject. For example, one method    includes providing to a subject an intraday peak-to-trough ratio of    (−)-halofenic acid of about 2.0 or less, comprising administering to    the subject arhalofenate (i.e. (−)-halofenate) by mouth in an oral    formulation (e.g. a tablet, capsule, pill, etc. as described above)    at a dose of 100 to 1000 mg per day.

Certain methods described herein may be accomplished by administering acompound of Formula (I), (II), (III) or (IV) or pharmaceuticallyacceptable salts thereof at a certain dose, frequency, and duration ofadministration, as provided herein. For example, certain methods providefor the treatment of hyperuricemia in a subject with gout comprisingadministering to a subject in need thereof a compound of Formula (I),(II), (III) or (IV) or pharmaceutically acceptable salts thereof whereinthe dose, frequency, and duration of administration are effective toreduce the number, duration, frequency, or intensity of gout flaresexperienced by the subject during the duration of administration. Insome embodiments, the compound is arhalofenate. In some embodiments thedose is from about 100 mg to about 1000 mg. In some embodiments thefrequency is daily. In some embodiments the duration of administrationis about 10 days or longer, about four weeks or longer, about one monthor longer, about 12 weeks or longer, about three months or longer, aboutsix months or longer, about one year or longer, about two years orlonger, about five years or longer, or about 10 years or longer. In someembodiments the administration may be indefinite, e.g. for the remainderof the lifetime of the subject. In some embodiments the administrationdaily and over a drug holiday of one day. In some embodiments furthercomprise administering to the subject arhalofenate by mouth in an oralformulation. Particular embodiments covering compositions, formulationsand their method of uses are disclosed in a PCT Patent Application No.PCT/US 11/59394 entitled “Methods for Treating Hyperuricemia in Patientswith Gout Using Halofenate or Halofenic Acid and a Second Urate-LoweringAgent” filed Nov. 4, 2011, and the PCT Application is incorporatedherein in its entirety.

In other aspects, the compounds and methods described herein may be usedto treat or prevent familial Mediterranean fever; thrombocytopenicpurpura; pericarditis; scleroderma; Behcet's disease; rheumatoidarthritis; familial cold autoinflammatory syndrome; Muckle-Wellssyndrome; chronic infantile neurologic, cutaneous and articularsyndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID);pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), and relateddisorders.

Methods

Methods used in relation to FIGS. 1-2 showing the pharmacokineticprofile of (−)-halofenic acid were as follows:

Plasma proteins in human plasma samples containing of (−)-halofenicacid, an internal standard (I.S.) and heparin as the anticoagulant wereprecipitated with acetonitrile. The samples were vortex mixed,centrifuged and an aliquot was analyzed by reversed phase highperformance liquid chromatography using a Phenomenex Polar RP columnmaintained at 45° C. The mobile phase was nebulized using heatednitrogen in a Z-spray source/interface and the ionized compounds weredetected using a tandem quadrupole mass spectrometer.

The plasma concentrations were rounded to the nearest one-tenth μg/mLbefore the calculations. Plasma samples with concentrations below thequantifiable limit of 1.0 μg/mL (BQL) were assigned values of zero.

Methods used in relation to FIG. 3 showing reduction in serum uric acidin subjects over time following once daily dosing with arhalofenate wereas follows.

A single centre Phase 1, placebo- and positive-controlled, double-blind,randomized, dose escalation study was conducted to evaluate themultiple-dose pharmacokinetics (PK) of (−)-halofenate administered as adaily dose orally for 10 days, at the protocol-specified doses inhealthy adult subjects. A total of 119 subjects completed studytreatment according to protocol: 6 subjects received (−)-halofenate 100mg/day for 10 days; 6 subjects received (−)-halofenate 200 mg/day for 10days; 9 subjects received (−)-halofenate 400 mg/day for 10 days; 20subjects received (−)-halofenate 600 mg/day for 10 days; 10 subjectsreceived (−)-halofenate 600 mg Enteric Coated (EC)/day for 10 days; 9subjects received (−)-halofenate 800 mg EC/day for 10 days; 10 subjectsreceived (−)-halofenate 1000 mg EC/day for 10 days; 24 subjects receivedplacebo treatment daily for 10 days; and 25 subjects received naproxen500 mg b.i.d. monotherapy for 7 days. In this study, serum uric acid wasmeasured at screening and on Days 1, 3, 5, 7, 9, 14 and 21.

TABLE 1 Mean Mean uric acid Mean uric acid change Treatment at baselineat Day 9 at Day 9 Mean % group N (mg/dL) (mg/dL) (mg/dL) change Placebo23 4.70 4.66 −0.04 −1  400 mg 10 4.91 3.89 −1.02 −21  600 mg 20 5.043.40 −1.65 −33  600 mg EC 10 5.61 3.92 −1.69 −30  800 mg EC 9 5.60 3.83−1.77 −32 1000 mg EC 10 5.48 3.04 −2.44 −45

As shown in FIG. 3 and Table 1, data from this study demonstrates thatthe treatment with (−)-halofenate resulted in gradual reduction in serumuric acid over a period of time at all dose levels tested, and in a dosedependent manner.

EXAMPLES Example 1 Suppression of Uric-Acid Induced Inflammation InVitro

Differentiated murine 3T3-L1 adipocytes are cultured in vitro in 24 wellplates. To the culture medium (−)-halofenic acid is added at a finalconcentration of 50-150 μM prior to the addition of uric acid at 5 mg/dLor 15 mg/dL and the culture continued for 3 or 7 days. A parallelculture of cells is conducted in the presence of a vehicle such asdimethylsulfoxide (DMSO). At the end of the culture period media isremoved, cells are isolated and messenger RNA prepared. The levels ofsecreted cytokines representing a panel of pro-inflammatory cytokinesincluding but not restricted to monocyte chemoatractant protein-1(MCP-1), tumor necrosis factor α (TNF-α), interlekin-1β, (IL-1β),interleukin-6 (IL-6) and interleukin-12 (Il-12) are determined in themedia isolated from the cells using commercially available cytokineassay kits. The levels of gene expression for the mRNAs for a panel ofpro-inflammatory cytokines including but not restricted to monocytechemoatractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α),interlekin-1β, (IL-1β), interleukin-6 (IL-6) and interleukin-12 (Il-12)are determined using real-time PCR. The addition of (−)-halofenateprevents the uptake of uric acid into 3T3-L1 adipocytes and therebysuppresses the uric acid induced inflammatory response resulting in areduced level of expression and consequently secretion of this panel ofpro-inflammatory cytokines. A similar study is also conducted in primarymouse macrophages and human umbilical vein endothelial cells.

Example 2 Animal Gout Hare Model

The models described in R. Torres et al., Ann Rheum. Dis. 68, 1602-08(2009) (available at http://ard.bmj.com/content/68/10/1602.1ong), whichis herein incorporated by reference in its entirety, is used. Briefly,twenty C57BL6 mice are obtained from Jackson Laboratories (Bar HarborMe. USA) and used between the ages of 12 and 16 weeks. The mice arehoused singly at least a week before study and allowed access to regularchow and water ad libitum. Arhalofenate is administered orally to half(ten) of the mice (test mice) daily at a dose of 125 mg/kg for periodsof time including for example 1 day, 5 days and 2 weeks prior toinduction of inflammation by uric acid. The remaining ten mice (controlmice) are administered a vehicle consisting of 1% CarboxymethylCellulose//2% Tween-80. In another treatment modality, arhalofenate isco-administered at the time of uric acid treatment.

Crystals of monosodium urate (MSU) are prepared as described in R.Liu-Bryan et al., Arthritis Rheum. 52, 2936-46 (2005). In one model, MSUcrystals (0.5 mg) suspended in 20 microliters of endotoxin-free PBS areinjected intro-articularly into the tibio-tarsal joint (ankle) of themice anaesthetized with 2.5% isoflurane. Thermal hyperalgesia, weightbearing ability, angle joint diameter, and histological analyses areperformed according to Torres et al, supra. The level of secretion of apanel of pro-inflammatory cytokines including but not restricted tomonocyte chemoatractant protein-1 (MCP-1), tumor necrosis factor α(TNF-α), interlekin-1β, (IL-1β), interleukin-6 (IL-6) and interleukin-12(Il-12) are measured in fluid isolated from the injected joints. Jointsare dissected and homogenized to allow preparation of mRNA and the levelof gene exrpression of the same panel of pro-inflammatory cytokinesdetermined. In another model, mice are injected intraperitoneally with 1mg of MSU suspended in 0.5 ml of endotoxin free PBS. After 6 h, mice arekilled and their peritoneal cavities washed and harvested formeasurement of neutrophil influx by staining with a neutrophil specificantibody R-phycoerythrin conjugated rat anti mouse Ly-6G monoclonalantibody. In another model, an air pouch is introduced subcutaneouslyand 1 mg of MSU is injected into the pouch. Six hours after crystalinjection the cells resident in the pouch are collected by lavaging with5 ml of buffer. Neutrophil infiltatation is measured by staining asabove. The levels of monocyte chemoatractant protein-1 (MCP-1), tumornecrosis factor α (TNF-α), interlekin-1β, (IL-1β), interleukin-6 (IL-6)and interleukin-12 (Il-12) are also measured in the lavaged fluidisolated from the urate injected air pouch.

Example 3 Clinical Trial Evaluating the Effectiveness of Arhalofenate atthe Doses of 400 mg and 600 mg Compared to Placebo in Serum Uric AcidReduction and Flare Prevention in Gout Patients with Hyperuricemia

Study Design: This was a randomized, double-blind, placebo-controlledstudy of 400 mg and 600 mg arhalofenate administered daily for 4 weeksas monotherapy in patients with gout (per criteria of the AmericanRheumatism Association) with hyperuricemia. Patients using uratelowering therapy (ULT) must have been willing to discontinue treatmentfor the duration of the study. Patients with a recent history of anacute gout flare must have been symptom free for at least 1 week priorto screening.

Upon successful completion of screening, patients entered into a minimum3-week Run-in/Stabilization Phase. During this phase, patients onexisting ULT were asked to temporarily discontinue their currenttherapy. Patients also started colchicine 0.6 mg once daily until thefinal study visit as prophylaxis to prevent potential gout flares.Patient who met final eligibility criteria were randomized (1:1:1) intothe Treatment Phase to receive Placebo, arhalofenate 400 mg, orarhalofenate 600 mg. Each randomized patient took double-blind studymedication daily for a period of four weeks beginning at Day 1 (Visit3). Patients returned to the study site after 2 weeks at Visit 4 andthen weekly at Visits 5 and 6 (Weeks 3 and 4). A Follow-up Visit (Visit7) took place 2 weeks after the last dose of study medication.

Diagnosis and Main Criteria for Inclusion: Male or female patients aged18 to 75 years, inclusive who had been diagnosed with gout and had ansUA ≧8.0 mg/dL and ≦12.0 mg/dL were eligible to participate in thisstudy. Patients with a recent history of an acute gout flare must havebeen symptom free for at least 1 week prior to both screening andrandomization.

Criteria for Evaluation:

The primary efficacy analysis compared the percentage change in sUA frombaseline to end of treatment between the treatment groups. In addition,gout flares were captured as special interest event and the incidence ofgout flares (all flares and flares that required treatment), severity(as assessed either mild, moderate, or severe by the PrincipalInvestigator), and duration (days) were compared between treatmentgroups.

Results:

All randomized patients in this study were male; mean ages ranged from50.9 years in the 400 mg arhalofenate group to 54.5 years in the placebogroup. The mean (±SD) time since the initial gout diagnosis was 7.1years [±6.7] in Placebo groups and 12.0 years [±8.2] in the 600 mgarhalofenate group. The mean (±SD) number of gout flares in thepreceding 3 months were 2.5 (±2.2), 1.4 (±1.2), and 2.1 (±2.4) for theplacebo, 400 mg arhalofenate, and 600 mg arhalofenate groups,respectively. The mean (±SD) sUA values at baseline (Day 1) were 9.7mg/dL (±1.6) in the placebo group, 9.4 mg/dL (±1.1) in the 400 mgarhalofenate group and 9.8 mg/dL (±1.3) in the 600 mg arhalofenategroup. A total of 67 (72.0%) patients were randomized to receivedouble-blind treatment: 23 patients received Placebo, 21 arhalofenate400 mg, and 23 arhalofenate 600 mg. A total of 64 patients completed thestudy: 22 patients in Placebo group, 20 patients in arhalofenate 400 mggroup, and 22 patients in arhalofenate 600 mg group. After 4 weeks ofdaily treatment with double-blind study medication, the mean sUA percent(and absolute) changes from baseline (Day 1) in the PP population were:4.1% (0.2 mg/dL) in the placebo group, -15.4% (1.4 mg/dL) in the 400 mgarhalofenate group and −23% (−2.3 mg/dL) in the 600 mg arhalofenategroup. When compared with placebo, the sUA reduction in both of thearhalofenate treatment groups was statistically significant (p<0.0001).A total of 10 patients reported flare during the Treatment Phase: 5patients (21.7%) in the placebo group, 4 patients (19.0%) in the 400 mgarhalofenate group, and 1 patient (4.3%) in the 600 mg arhalofenategroup [FIG. 4]. Of these, 3 patients (13.0%) in the placebo group, 1patient (4.8%) in the 400 mg arhalofenate group, and 1 patient (4.3%) inthe 600 mg arhalofenate group required medication (additional colchicineand/or NSAIDs) [FIG. 4]. The mean duration of Total flares was longer inthe placebo group (5.2 days) than in either the 400 mg arhalofenategroup (1.3 days) or the 600 mg arhalofenate group (1.0 days) [FIG. 5].The mean (±SD) duration of Flares Requiring Treatment was also longer inthe placebo group (4.7 days) than in either the 400 mg arhalofenategroup (2.0) or the 600 mg arhalofenate group (1.0 day) [FIG. 5]. Nosevere gout flare was reported during the double-blind period. Flareswere less severe in the arhalofenate 600 mg group compared to othergroups (3 of 5 flares in placebo group, 2 of 4 flares in 400 mgarhalofenate group and 0 of 2 flares in 600 mg arhalofenate group wereconsidered moderate in severity by the investigator).

Example 4 Clinical Trial Evaluating the Effectiveness of Arhalofenate inCombination With Febuxostat Compared to Febuxostat Alone in Serum UricAcid Reduction and Flare Prevention in Gout Patients with Hyperuricemia

Study Design: This was an open-label study to determine the sUAreduction and flare prevention with arhalofenate in combination withfebuxostat and compared that with febuxostat alone in gout patients (percriteria of the American Rheumatism Association) with hyperuricemia whenarhalofenate administered at 400 mg once daily orally for 2 weeks (Weeks2-3) and then increased to 600 mg once daily orally for an additional 2weeks (Weeks 4-5) in addition to 80 mg febuxostat once daily orally(Weeks 1-5). Patients with a recent history of an acute gout flare musthave been symptom free for at least 1 week prior to screening.

All patients who met the screening criteria started a 2-weekRun-in/Stabilization Phase at the same time as out-patient basis. Duringthis phase, patients on existing urate lowering therapy were asked todiscontinue their current therapy for the duration of the study. At thesame time, patients also started colchicine 0.6 mg once daily asprophylaxis to prevent potential gout flares. Upon completing theRun-in/Stabilization Phase, patients were reassessed at Day-2 (Visit 2)to confirm the final eligibility for the Treatment Phase. The sUA atthis visit must have been ≧8.0 mg/dL and ≦10 mg/dL to qualify for theTreatment Phase. In addition, all safety lab values must have met theeligibility criteria at this visit. Patients successfully meeting theeligibility criteria entered the study site for an in-clinic stay for atotal of 37 consecutive days.

The Treatment Phase began on Day 1 and continued for 5 weeks until Day35. The Treatment Phase consisted of 3 sequential drug dosing periods:

80 mg febuxostat orally once daily from Days 1 through 7 (FebuxostatPeriod).

80 mg febuxostat plus 400 mg arhalofenate orally once daily from Days 8through 21(Febuxostat plus 400 mg arhalofenate Period).

80 mg febuxostat plus 600 mg arhalofenate orally once daily from Days 22through 35 (Febuxostat plus 600 mg arhalofenate Period).

In addition, all patients continued to receive 0.6 mg colchicine dailyfor gout flare prophylaxis.

Criteria for Evaluation:

Efficacy of febuxostat plus arhalofenate combination treatment wasassessed by the proportion of patients achieving a sUA <6 mg/dL, <5mg/dL, <4 mg/dL, and <3 mg/dL at Day 22 and Day 36. In addition,absolute and percent changes in sUA at Day 22 and Day 36 from baseline(Day 1) were also evaluated. Gout flares were captured as specialinterest event in this study. The incidence of gout flares, severity (asassessed either mild, moderate, or severe by the PrincipalInvestigator), and duration (days) were compared between treatmentperiods.

Results:

A total of 12 patients met the final eligibility criteria at Visit 2(Day-2) and entered into the in-patient Treatment Phase of the study asa single cohort. On Day 1, after receiving the first dose of febuxostat,1 patient withdrew consent to continue study participation for personalreason (got a permanent job); the remaining 11 patients completed thestudy including Follow-up phase. The mean (±SD) time since the initialgout diagnosis was 12.6 years (±7.2). The mean (±SD) number of goutflares in the preceding 3 months was 0.9 (±1.2). The mean (±SD) sUA atbaseline was 9.0 mg/dL (±0.8). At Day 8, after one week of dailytreatment with 80 mg febuxostat, 11 patients (100%) reached sUA targetof <6 mg/dL, 6 patients (55%) reached <5 mg/dL, and 1 patient (9%)reached <4 mg/dL. At Day 22, after 2 weeks of daily treatment with 80 mgfebuxostat plus 400 mg arhalofenate (preceded by 80 mg febuxostat dailyfor 1 week), statistically significantly higher proportion of patientsachieved sUA target of <5 mg/dL compared with Day 8 (sUA <5.0 mg/dL in10 patients, p=0.0455). By Day 36, after 2 weeks of daily treatment with80 mg febuxostat plus 600 mg arhalofenate (preceded by 80 mg febuxostatdaily for 1 week and 80 mg febuxostat plus 400 mg arhalofenate for 2weeks), statistically significantly higher proportion of patientsachieved sUA targets of <5 mg/dL and <4 mg/dL compared with Day 8 (sUA<5.0 mg/dL in 11 patients, p=0.0253; sUA <4.0 mg/dL in 7 patients,p=0.0143).

In this study, gout flare was considered as a special interest event.All patients were taking 0.6 mg colchicine daily as flare prophylaxisfor the entire duration of the study. Overall, 4 patients experiencedgout flares during the study—2 patients during 1 week of febuxostat onlyperiod, 2 patients during 2 weeks of 400 mg arhalofenate plus febuxostatperiod. No patient reported flare during 2 weeks of 600 mg arhalofenateplus febuxostat period. When adjusted by duration of treatment, 18.2%patients/week during febuxostat only period, and 9.1% patients/weekduring 400 mg arhalofenate plus febuxostat period reported flare [FIG.6]. Mean duration of the gout flares during the Treatment Phase was 6.5days for the febuxostat only period and 4.0 days for the 400 mgarhalofenate plus febuxostat period [FIG. 7]. All of the flares weremild or moderate in severity.

Example 5 Clinical Trial to Evaluate the Role of ArhalofenateMonotherapy (600 Mg and 800 mg) in Preventing Gout Flare and ReducingsUA in Gout Patients when Used as a Urate Lowering Agent and Comparethat with Allopurinol 300 Mg

Study Design: This is a multi-center, randomized, double-blind, activeand placebo-controlled, parallel group study in gout patients with sUAof >7.5 mg/dL and <12 mg/dL who experienced at least 3 flares during thepast 12 months. Approximately 225 eligible patients will be randomizedin a 2:2:2:2:1 ratio into one of the following five treatment groups:

1) Arhalofenate (600 mg) once daily.

2) Arhalofenate (800 mg) once daily.

3) Allopurinol (300 mg) plus colchicine (0.6 mg) once daily.

4) Allopurinol (300 mg) once daily.

5) Placebo once daily.

Study Objectives:

Primary:

To evaluate the efficacy of each of two dose levels of arhalofenatedosed once daily for the prevention of flares in adult gout patientswith hyperuricemia.

Secondary:

To evaluate the efficacy of each of two dose levels of arhalofenate inreducing serum uric acid (sUA).

To evaluate whether arhalofenate can effectively reduce acute goutflares without colchicine prophylaxis.

To evaluate the safety and tolerability of each of two dose levels ofarhalofenate in this study population.

To select an appropriate dose level of arhalofenate dosed once daily forfuture trials

To measure steady-state arhalofenate concentrations at each of two doselevels of arhalofenate dosed once daily.

To evaluate changes in metabolic parameters of interest in selectedpatients.

Study Endpoints:

Primary

The incidence of gout flares (mean number of flares per patient) frombaseline through Week 12.

In this study, a gout flare is defined as a patient-reported acutearticular or bursal pain at rest (exceeding 3.0 cm on a 10.0 cm VAS)typical of a gout attack and deemed (by patient and/or investigator) torequire treatment with an anti-inflammatory therapeutic agent, and thepresence of at least 2 of the following 3 signs or symptoms: jointswelling, warmth, and tenderness; and at least one of the following:rapid onset of pain, decreased range of motion, redness, or othersymptoms similar to a prior gout flare.

Secondary

Key Secondary endpoints:

Percent sUA reduction from baseline in arhalofenate 800 mg groupcompared to Placebo group.

Percent sUA reduction from baseline in arhalofenate 600 mg groupcompared to Placebo group.

Proportion of patients with sUA <6 mg/dL at Week 12 in arhalofenate 800mg group compared to Placebo group.

The incidence of gout flares from baseline through Week 12 inarhalofenate 600 mg group compared to allopurinol 300 mg group.

Proportion of patients with sUA <6 mg/dL at Week 12 in arhalofenate 600mg group compared to Placebo group.

Proportion of patients experiencing at least one flare from baselinethrough week 12.

Proportion of patients experiencing multiple flares from baselinethrough week 12.

Time from baseline to first flare.

The incidence of flares from baseline through Week 4, Week 5 throughWeek 8 and

Week 9 through Week 12.

Flare composite score (summation of the daily maximum pain severity onVAS during the duration of the flare).

Evaluation of activity limitation during flare via HAQ-II.

Changes from baseline through week 12 in HbA1c and fasting TG inpatients with HbA1c >7.0% and TG>150 mg/dL at baseline, respectively.

Adverse events, and changes in vital signs and safety laboratory tests.

Safety-related study drug discontinuations.

Flare-related study drug discontinuations.

Flares that occur during the study will be managed with oral NSAIDs (as1^(st) line therapy) or oral steroids (as 2^(nd) line therapy) if thepatient cannot tolerate or has an inadequate response to NSAIDs. Thepatient will be allowed to take other analgesics, according toinvestigator judgment (e.g. acetaminophen with codeine), as 3^(rd) linetherapy if the patient cannot tolerate or has an inadequate response toNSAIDs and oral steroids. Colchicine will be prohibited as treatment forflares during the randomized treatment phase.

All patients will be instructed to maintain their current diet andlifestyle, including drinking habits (alcoholic and sugary beverages),throughout the entire study. Patients will be asked to defer initiatingany weight loss diets or meaningfully changing their activity level andlifestyle, as such a change may influence sUA levels and potentiallytrigger a flare, thus confounding a trial of this nature.

Once randomized (entered) into the study, patients will return to theclinic within 7 days to receive study drug supplies and begin dosing(Day 1). Subsequent study visits will occur at the end of week 2, week4, week 8, and week 12 of dosing.

The patient will be required to report a flare via an electronic deviceas soon as conveniently possible and preferably before taking painmedication. Flare-related data, such as date and time of onset, painseverity (VAS), and medication taken will be reported by the patient.Once flare data has been entered by the patient, the device will send analert to the investigator or his/her designee to contact the patient inorder to facilitate additional therapy or data entry, as needed.

Sample Size:

This study is powered to detect a treatment group difference in flarerate (flares per patient) of 50% versus the control group (group 4,allopurinol 300 mg). Power calculations (using methodology forcomparisons of incidence rates) indicate that a sample size of 50patients per treatment group should provide 80% power, based on the useof a two-sided, two-sample test at the 5% level of significance, todetect a 50% treatment group difference, which is a conservativeestimate of the expected treatment effect.

In this study, the placebo control group will be used for sUAcomparisons (percent reduction and proportion of patients achieving sUA<6 mg/dL) only. Power calculations indicate that a sample size of 25patients in this arm should provide 80% power, based on the use of atwo-sided, two-sample test at the 5% level of significance, to detect a50% treatment group difference.

Efficacy Analyses:

For the efficacy endpoint of flare rate (mean flare per patient from Day1 through week 12), the primary analysis will compare the arhalofenate800 mg group to the allopurinol 300 mg group using a two-sided test atthe 5% level of significance.

The following key secondary analyses will be conducted using ahierarchical procedure (Westfall and Krishen 2001) to control theoverall level of significance, in the order shown below:

Arhalofenate 800 mg group vs Placebo for percent sUA reduction.

Arhalofenate 600 mg group vs Placebo for percent sUA reduction.

Arhalofenate 800 mg group vs Placebo for proportion of patients with sUA<6 mg/dL.

Arhalofenate 600 mg group vs Allopurinol 300 mg for flare rate.

Arhalofenate 600 mg group vs Placebo for proportion of patients with sUA<6 mg/dL.

The above hypotheses will be tested using two-sided tests at the 5%level of significance, but a specified comparison will only be tested ifthe primary efficacy analysis and all previously conducted key analysesare statistically significant (p<0.05).

While the foregoing description describes specific embodiments, thosewith ordinary skill in the art will appreciate that variousmodifications and alternatives can be developed. Accordingly, theparticular embodiments and examples described above are meant to beillustrative only, and not to limit the scope of the invention, which isto be given the full breadth of the appended claims, and any and allequivalents thereof.

What is claimed is: 1-18. (canceled)
 19. A method for treating a goutflare experienced by a subject comprising administering to the subject acompound of Formula (I)

wherein R is selected from the group consisting of a hydroxy, loweralkanamido-lower alkoxy; and each X is independently a halogen; or apharmaceutically acceptable salt thereof.
 20. The method of claim 19,wherein the compound or a pharmaceutically acceptable salt thereof is(−)-halofenate or (−)-halofenic acid, or a pharmaceutically acceptablesalt thereof.
 21. The method of claim 19, wherein the compound is(−)-halofenate.
 22. A method for reducing the number, duration,frequency or intensity of gout flares experienced by a subjectcomprising administering a compound of Formula (I) of claim 19 or apharmaceutically acceptable salt thereof to the subject.
 22. The methodof claim 19, wherein the compound is (−)-halofenate or (−)-halofenicacid, or a pharmaceutically acceptable salt thereof.
 23. The method ofclaim 19, wherein the compound is (−)-halofenate.
 24. A method for thetreatment of hyperuricemia in a subject with gout comprisingadministering to a subject in need thereof a compound of Formula (I) ofclaim 19 wherein the dose, frequency, and duration of administration areeffective to reduce the number, duration, frequency, or intensity ofgout flares experienced by the subject during the duration of theadministration.
 25. The method of claim 24, wherein the compound or apharmaceutically acceptable salt thereof is a compound of Formula (II)

wherein R² is lower alkanamido-lower alkyl; and each X is independentlya halogen; and each X is independently a halogen; or a pharmaceuticallyacceptable salt thereof.
 26. The method of claim 24, wherein thecompound is (−)-halofenate or (−)-halofenic acid, or a pharmaceuticallyacceptable salt thereof.
 27. The method of claim 24, wherein thecompound is (−)-halofenate.
 28. The method of claim 24, wherein thecompound is (−)-halofenate and the compound is administered at fromabout 400 mg to about 1000 mg per day.
 29. The method of claim 24,wherein the duration of the administration is about 12 weeks.
 30. Themethod of claim 24, further comprising the administration of a secondurate-lowering agent selected from the group consisting of a xanthineoxidase inhibitor, an inhibitor of uric acid production, a uricosuricagent and a uricase.
 31. The method of claim 30, wherein the secondurate-lowering agent is selected from the group consisting ofallopurinol, febuxostat, ulodesine, forodesine, oxypurinol, tisopurine,inositol, phytic acid, myo-inositiol, kaempferol, myricetin, quercetin,probenecid,2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, potassium4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetamido)-3-chlorobenzoate,RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin,fenofibrate, levotofisopam, guaifenesin, losartan, adrenocorticotropichormone and cortisone.
 32. The method of claim 30, wherein secondurate-lowering agent is febuxostat.
 33. The method of claim 30, whereinthe first urate-lowering agent is (−)-halofenate and is administered atfrom about 400 mg to about 800 mg per day, and the second urate-loweringagent is febuxostat and is administered at from about 40 mg to about 120mg per day.
 34. A method of providing to a subject (−)-halofenic acidwith an intraday peak-to-trough ratio of about 2.0 or less, comprisingadministering to the subject from about 100 mg to about 1000 mg per dayof a compound of Formula (I) of claim 19 or a pharmaceuticallyacceptable salt thereof.